Dale and Norenberg and Waugh et al. Red cells are labeled ex vivo and infused into animals or labeled by intravenous injection of biotin in vivo. At various time intervals, the biotinylated red cells can be isolated using an avidin matrix.
Studies of biotinylated rabbit red cells showed that old cells had both decreased surface area The aged cells were found to have normal membrane elasticity with only a minority of the cells being recovered from denser fractions following centrifugation.
A rapid and robust method compliant with good practice guidelines was developed to generate biotin-labeled red cells for clinical research de Back et al. Furthermore, a stable isotope-based mass spectrometric method using non-radioactive 15N-glycine for cohort labeling has been developed and it do not involve membrane modification or radioactivity Browne et al.
This method show good correlation with the biotin method Khera et al. We expect that application of these procedures will advance our understanding of the molecular basis of red cell aging in humans by providing a uniform approach to analysis of erythrocyte physiology and pathophysiology. Band 3 SLC4A1 is the most abundant integral membrane protein in the red cell with more than a million copies per cell.
It is a amino acid glycoprotein and the founding member of the anion exchanger gene family AE In the membrane, Band 3 associates with a number of other membrane proteins including the Rh complex, glycophorins, and CD On the cytoplasmic side, it attaches to the membrane cytoskeleton through interactions with Band 4.
This process is reversed in the lungs. The crystal structure of transmembrane domain of Band 3 has been solved, providing insights into its functional interactions Hatae et al. Deoxyhemoglobin binds to Band 3 and this interaction is implicated in sensing changes in oxygen tension and controlling red cell deformability thereby capillary velocity during hypoxia Zhou et al.
Furthermore, this interaction is also implicated in senescence induced clearance. Alteration in Band 3 has been studied as senescent tag for macrophage recognition and clearance if senescent red cells. Oxidant stress-mediated denaturation of hemoglobin produces hemichromes that accumulate in the cytoplasm and copolymerize with the cytoplasmic domain of Band 3, forming an insoluble macromolecular aggregate Low et al. Oxidation of hemichrome-mediated clustering of Band 3 is thought to expose neoantigens that are recognized by naturally occurring antibodies and cleared by macrophages.
In addition to hemichrome-induced clustering, calcium-dependent proteolytic degradation of Band 3 has been postulated to expose a senescent tag Kay et al. Furthermore, Band 3 clustering has been proposed to bind to an endothelial cell receptor for products of advanced glycation Wautier and Wautier, Naturally occurring antibodies 39 have germline immunoglobulin sequences that are polyreactive, binding with low affinity to multiple epitopes Turman et al. Numerous functions have been attributed to these antibodies, including serving as the first line of defense against pathogens, clearance of cellular debris, and recognition of oxidation-specific epitopes in lipids and proteins.
Naturally occurring antibodies that bind to clustered Band 3 or neoantigens in Band 3 have been proposed as mediators of senescent red cell clearance Kay, ; Lutz, Studies by Kay et al. Old red cells were reported to have autologous serum antibodies bound to discrete regions of Band 3 localized to amino acids — and — Kay and Lin, In addition to antibodies against Band 3, naturally occurring antigalactosyl antibodies have been postulated to bind these cryptic antigens exposed at senescence Galili et al.
However, there is no alteration in red cell clearance in agammaglobulinemic mice, questioning the physiological significance of antibody-mediated clearance of senescent red cell Connor et al. Advances in proteomics should further refine analysis of changes in Band 3 during aging in vivo Bosman et al. Band 4.
Inaba et al. Deamidation may induce conformational changes that alter the functional characteristics of Band 4. The 78 kDa form 4. Mueller et al. They showed that during in vivo aging, there is an increase in the ratio of 4. The ratio of 4. CD47 is a heavily glycosylated cell surface protein belonging to the immunoglobulin superfamily that is present in red cells in complex with Rh proteins Oldenborg, CD47 deficient red cells are rapidly cleared from the peripheral circulation by splenic macrophages in a process that is independent of complement and antibodies Oldenborg et al.
Physiologically, CD47 functions to prevent autologous cells from undergoing phagocytosis Jaiswal et al. Changes in CD47 have been investigated in relation to erythrocyte storage and senescence. CD47 was reported to be lost from human erythrocytes during storage Anniss and Sparrow, , and the density of CD47 was reported to decrease during aging of murine erythrocytes surface Khandelwal et al. However, Rh null cells with reduced CD47 expression do not show heightened interaction with monocytes Arndt and Garratty, Furthermore, in autoimmune hemolytic anemia, CD47 expression is normal Ahrens et al.
Desialylation of membrane proteins was among the first mechanisms postulated to account for clearance of senescent red cell Aminoff et al. Most erythrocyte membrane proteins are rich in sialic acid, which gives the cell a negative charge.
It was hypothesized that progressive loss of sialic acid occurred as red cells age thereby providing a marker of senescence and a mechanism for recognition and clearance aged erythrocytes. Despite demonstration that enzymatic desialylation of red cells results in rapid clearance, sialic acid content does not change significantly as erythrocytes age Shinozuka et al. This interaction is inhibited by sialic acid moieties of glycophorin C, a minor erythrocyte membrane glycoprotein Jaskiewicz et al.
Asymmetrical distribution of phospholipids is a common property of all mammalian cells. In the case of red cells, anionic phospholipids reside in the inner leaflet while neutral or zwitterionic phospholipids predominantly comprise the outer leaflet Bretscher, ; Verkleij et al.
Phosphatidylserine exposure in the outer leaflet is the basis of recognition of apoptotic cells by the macrophages Penberthy and Ravichandran, Schroit et al. These cells accumulated in splenic macrophages and hepatic Kupffer cells. However, clearance was incomplete, and this observation was attributed to aminophospholipid translocase activity, which continuously pumps phosphatidylserine to the inner leaflet of the circulating cells, thereby preventing red blood cell recognition by macrophages.
Using annexin V binding to quantify phosphatidylserine exposure by biotin labeled red cells, Boas et al. Other studies, however, have not shown a greater phosphatidylserine in aged red cells compared to their younger counterparts Wesseling et al. One explanation for these disparate observation is that phosphatidylserine-expressing red cells are removed from the circulation by macrophages at a rate that makes them undetectable Schroit et al.
Conceivably disturbances in mechanisms involved in the maintenance of membrane phospholipid could contribute to red cell senescence. P-type ATPases flipases catalyze the transport of phospholipids from the outer to the inner leaflet, Sebastian et al.
Another enzyme, scramblase, that facilitates movement of lipids between both leaflets, has been identified. Lipid scrambling changes the architecture of the bilayer, promoting exposure of phosphatidylserine and release of extracellular vesicles Nagata et al.
A number of mechanisms have been proposed to explain phosphatidylserine exposure during red cells senescence. Oxidation of phosphatidylserine alters its ability to act as a substrate for aminophospholipid translocase, which transports phosphatidylserine from the outer to inner leaflet Tyurina et al.
Aging of erythrocytes increases both membrane lipid peroxidation Ando et al. The cytoskeleton in an important component of the process by which lipid asymmetry is maintained. Phosphatidylserine interacts with the major membrane cytoskeletal protein, spectrin Kunzelmann-Marche et al. Disruption of membrane-cytoskeletal interactions, due to senescence-induced aggregation of Band 3, may result in phosphatidylserine exposure.
In a mouse model, widespread thrombosis and severe hemolysis due to increased phosphatidylserine exposure was observed in Band 3 null red cells Hassoun et al. However, in hereditary spherocytosis, erythrocytes fully conserve lipid asymmetry despite abnormalities in membrane skeleton components Calvez et al. This observation suggests that the contribution of cytoskeletal proteins to regulation of phosphatidylserine is insignificant. On the other hand, clustering of Band 3 has bee reported to induce externalization of phosphatidylserine by a calcium- and oxidation-independent mechanism Koshkaryev et al.
Eryptosis is the process of cell shrinkage and exposure of phosphatidylserine due influx of calcium ions that activates a scramblase resulting in redistribution of phospholipids in both leaflets Lang et al. Eryptosis may contribute to red cell clearance in diseased states, but its contribution to senescence-associated clearance is speculative. Physiological processes that delay senescence may contribute to hypoxia-induced erythrocytosis Tang et al.
The studies provided the first evidence suggesting that longer red cell survival, in addition to hypoxia stimulation of erythropoiesis contributes to hypoxia-induced erythrocytosis. Lactadherin, also called milk fat globule epidermal growth factor 8, is an opsonin that binds to phosphatidylserine expressing cell, including red cells Hanayama et al.
It has a phosphatidylserine binding domain, as well as an Arginine-Glycine-Aspartic acid RGD motif in one of its epidermal growth factor domains which mediates binding to integrins Andersen et al.
Lactadherin-mediated erythrophagocytosis of phosphatidylserine expressing cells by integrins is proposed as a mechanism for clearance of senescent red cells by activated endothelial cells Fens et al. However, red cell survival is normal in lactadherin deficient mice, and as discussed above, whether senescent red cells express greater amounts of phosphatidylserine is an issue of active debate Dasgupta et al.
Physiologic response to hypoxia is the stimulation of red blood cell production. Hypoxia-inducible factors HIFs orchestrate response to hypoxia and HIF-2 is the principal regulator of erythropoietin EPO production in kidney as underscored by genetic studies in human populations that live at high-altitude and by mutational analysis of patients with familial erythrocytosis Prchal, Upon the rapid return to normoxia, the secondary erythrocytosis is overcorrected, as the accumulated, newly formed red cells undergo preferential destruction.
This process, termed neocytolysis , was originally observed in astronauts returning to earth after living in a zero gravity environment Rice et al.
Return to normoxia from hypoxia results in generation of reactive oxygen species from increased mitochondrial mass that correlates with decreased expression of Bnip3L transcripts, a hypoxia regulated gene Sandoval et al. Bnip3L mediates removal of reticulocyte mitochondria that generate increased reactive oxygen species accompanied by reduced catalase activity mediated by hypoxia-regulated miR21 Song et al.
Rapid changes in hematocrit in human newborns also suggest that neocytolysis also occurs after birth. The hypoxic fetus has erythrocytosis at birth, but the neonate rapidly overcorrects its elevated red cell mass and becomes anemic in first 2 weeks of life Christensen et al. In contrast to our limited understanding of the physiological red blood cell clearance of senescent red cells, the mechanisms involved in removal of abnormal erythrocytes hemolysis are understood in greater details.
Premature destruction can occur in the circulation by lysis with the release of hemoglobin into the plasma intravascular hemolysis or by the macrophages in the spleen and liver extravascular hemolysis with little release of hemoglobin. The spleen plays a major role here. Increased splenic clearance occurs due to injuries extrinsic events immunological targeting, mechanical or chemical injuries or due to intrinsic defects in red cells due to inherited defects in red cells cytoskeleton or enzymes.
Red cells with reduced deformability are unable to negotiate through narrow endothelial slits in the human spleen. Consequently, they are retained in the splenic cords and eventually destroyed by red pulp macrophages. The principal determinants of the red blood cell deformability are the ratio of cell surface area to volume determined by the shape , intracellular viscosity determined the physical properties of hemoglobin , and membrane elasticity determined by rheological properties of the membrane.
As discussed earlier, red cells traverse the interendothelial slit in splenic sinusoids. When normal deformity is compromised, sustained elongation results in loss of membrane due to vesiculation Li et al. Premature destruction occurs in many membrane disorders including hereditary spherocytosis, ovalocytosis, and pyropoikilocytosis.
In addition to intrinsic membrane defects, the red cell membrane can be damaged by abnormalities in microcirculation due intravascular fibrin deposition and abnormal shearing due artificial heart valves, or severe aortic stenosis.
The fragment erythrocytes are rapidly removed by the reticuloendothelial system. Collectively these processes are called microangiopathic hemolytic anemia. Red cells efficiently transport oxygen throughout their lifespan unless they are damaged by ROS. Consequently, they have effective mechanism to quench ROS. Depletion of NADPH can occur in the G6PD deficiency, or structural hemoglobin abnormalities that predispose to hemoglobin oxidation, or exposure to oxidant drugs.
Oxidation of hemoglobin alters the quaternary structure allowing them to precipitate within the red cell and to form aggregates called Heinz bodies. Heinz bodies attach to the red cell membrane decreasing deformability, thereby rendering the affected cells susceptible to engulfment by sinusoidal macrophages of the spleen and liver to membranes decreases the deformability and other physical properties pliable of red cell membrane, rendering them to engulfment by macrophages in rich sinusoids of spleen and liver.
Macrophage-mediated removal of Heinz bodies leaves a defect in the erythrocyte membrane structure that may be seen as bite cells on microscopic examination of the peripheral blood smear. Antibody-mediated intravascular hemolysis occurs due to complement activation by the classical pathway. IgM antibodies fix complement more avidly than IgG antibodies because of their they are pentavalent rather than bivalent.
Hence, the antigen density is a critical determinate of complement activation in IgG-mediated immune hemolytic anemia Garratty, As the macrophages do not express IgM Fc receptors Kubagawa et al. Immune complexes activate the classical complement pathway by binding the C1q portion of the C1 complex. Exposure of the collagen-like regions of C1q makes it recognizable by macrophage complement receptor 1 CR1 Eggleton et al.
Rather, during complement activation, the third component of complement C3 is cleaved to C3b, which can bind covalently to cell surface carbohydrate and peptide moieties. Bound C3b is rapidly cleaved to an inactivated form, iC3b. Cell bound iC3b is rapidly degraded enzymatically to C3dg and C3d. For more resources, visit www.
This information explains the different parts of your blood and their functions. Your blood is made up of 4 parts: red blood cells, white blood cells, platelets, and plasma.
Parts of Your Blood Red blood cells erythrocytes Red blood cells carry oxygen from your lungs to your tissues. White blood cells leukocytes White blood cells fight infection and are an important part of your immune system.
There are 3 types of granulocytes: Neutrophils help fight bacterial and fungal infections. Eosinophils help fight infections caused by parasites.
Monocytes break down and remove foreign organisms and dying cells from your body. Lymphocytes make up your immune system. White blood cells have a wide range of lifespans, from hours to years. Platelets thrombocytes Platelets are small parts of cells. An oxygen deficit in the brain impairs the ability to think clearly, and may prompt headaches and irritability.
Lack of oxygen leaves the patient short of breath, even as the heart and lungs work harder in response to the deficit. Blood loss anemias are fairly straightforward. In addition to bleeding from wounds or other lesions, these forms of anemia may be due to ulcers, hemorrhoids, inflammation of the stomach gastritis , and some cancers of the gastrointestinal tract. The excessive use of aspirin or other nonsteroidal anti-inflammatory drugs such as ibuprofen can trigger ulceration and gastritis.
Excessive menstruation and loss of blood during childbirth are also potential causes. Anemias caused by faulty or decreased RBC production include sickle cell anemia, iron deficiency anemia, vitamin deficiency anemia, and diseases of the bone marrow and stem cells.
Figure 5. Sickle Cells Sickle cell anemia is caused by a mutation in one of the hemoglobin genes. Erythrocytes produce an abnormal type of hemoglobin, which causes the cell to take on a sickle or crescent shape. It can occur transiently in a person who is dehydrated; when water intake is inadequate or water losses are excessive, the plasma volume falls. As a result, the hematocrit rises. For reasons mentioned earlier, a mild form of polycythemia is chronic but normal in people living at high altitudes.
Some elite athletes train at high elevations specifically to induce this phenomenon. Polycythemia vera can dangerously elevate the viscosity of blood, raising blood pressure and making it more difficult for the heart to pump blood throughout the body. It is a relatively rare disease that occurs more often in men than women, and is more likely to be present in elderly patients those over 60 years of age.
The most abundant formed elements in blood, erythrocytes are red, biconcave disks packed with an oxygen-carrying compound called hemoglobin. The hemoglobin molecule contains four globin proteins bound to a pigment molecule called heme, which contains an ion of iron. In the bloodstream, iron picks up oxygen in the lungs and drops it off in the tissues; the amino acids in hemoglobin then transport carbon dioxide from the tissues back to the lungs.
Erythrocytes live only days on average, and thus must be continually replaced. Worn-out erythrocytes are phagocytized by macrophages and their hemoglobin is broken down. The breakdown products are recycled or removed as wastes: Globin is broken down into amino acids for synthesis of new proteins; iron is stored in the liver or spleen or used by the bone marrow for production of new erythrocytes; and the remnants of heme are converted into bilirubin, or other waste products that are taken up by the liver and excreted in the bile or removed by the kidneys.
Answer the question s below to see how well you understand the topics covered in the previous section. Show Answers. Skip to main content. Chapter The Cardiovascular System. Search for:. Erythrocytes Learning Objectives By the end of this section, you will be able to: Describe the anatomy of erythrocytes Discuss the various steps in the lifecycle of an erythrocyte Explain the composition and function of hemoglobin.
Figure 1. Summary of Formed Elements in Blood. Critical Thinking Questions young woman has been experiencing unusually heavy menstrual bleeding for several years. She follows a strict vegan diet no animal foods. Miller, R. You can also search for this author in PubMed Google Scholar.
Reprints and Permissions. Bard, H. Pediatr Res 42, 9—11 Download citation. Received : 17 January Accepted : 02 April Issue Date : 01 July Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.
Annals of Hematology Journal of Perinatology Advanced search. Skip to main content Thank you for visiting nature. Download PDF. Abstract This study was made to determine the life span of adult red cells transfused to early preterm infants.
Main During their first few months of life, early preterm infants are among the most common of all patient groups to undergo transfusions 1. Table 1 Characteristics of the 19 early preterm study infants Full size table.
Figure 1. Full size image. Figure 2. References 1 Strauss RG Transfusion therapy in neonates. Google Scholar 3 Mollison PL The survival of transfused erythrocytes in haemolytic disease of the newborn. Article Google Scholar 5 Ashby W The determination of the length of life of transfused blood corpuscles in man.
Google Scholar 11 Bard H Postnatal fetal and adult hemoglobin synthesis in early preterm newborn infants. Article Google Scholar Download references. Acknowledgements The authors thank the research nurses, including Karen J.
View author publications. Rights and permissions Reprints and Permissions. About this article Cite this article Bard, H. Copy to clipboard.
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